1-Piperidinecarboxaldehyde → 2-Methoxy-5-(methoxymethoxy)-4-pyridinecarboxaldehyde

Temperature

-40 °C

To a solution of 2-methoxy-5-(methoxymethoxy)pyridine (20 g, 0.12 mol) in THF was added diisopropylamine (0.24 g, 2.4 mmol). The solution was cooled to −40° C. followed by addition of MeLi (3M/THF, 72 mL, 0.216 mol) slowly. The resulting mixture was warmed to 0° C., stirred at 0° C. for 3 h, cooled back down to −40° C. and added N-formylpiperidine (24 mL, 0.216 mol). After stirring at −40° C. for 2 h, the mixture was quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL). The temperature was then raised to rt and diluted with water (200 mL) and EtOAc (200 mL). The pH of the mixture was adjusted to 8-9 with solid K2CO3 and extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2SO4, and concentrated. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 42%) as a pale yellow oil. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H).

1. temperatureThe resulting mixture was warmed to 0° C.
2. temperaturecooled back down to −40° C.
3. stirringAfter stirring at −40° C. for 2 h
4. customthe mixture was quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL)
5. temperatureThe temperature was then raised to rt
6. additiondiluted with water (200 mL) and EtOAc (200 mL)
7. extractionextracted with EtOAc (300 mL) twice
8. dry with materialdried over Na2SO4
9. concentrationconcentrated
10. customThe residue was purified on silica gel with 25% EtOAc/hexanes as eluent

ORD record

ord-b8101d95558d4e7d8a9bddaee21a5746

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012450B2